The present invention relates to new dihydropyridine derivatives, and the use of the dihydropyridine derivatives as medicines. It is said that the activation of N-type calcium channel is concerned with diseases such as encephalopathies caused by the ischemia in the acute phase after the onset of cerebral infarction, cerebral hemorrhage (including subarachnoidal bleeding) or the like; progressive neurodegenerative diseases, e.g. Alzheimer""s disease; AIDS related dementia; Parkinson""s disease; dementia caused by cerebrovascular disorders and ALS; neuropathy caused by head injury; various pains, e.g. sharp pain caused by spinal injury,diabetes or thromboangitis obliterans; pain after an operation; migraine and visceral pain; various diseases caused by psychogenic stress, e.g. bronchial asthma; unstable angina and hypersensitive colon inflammation; emotional disorder; and drug addiction withdrawal symptoms, e.g. ethanol addiction withdrawal symptoms. The compounds of the present invention are effective in inhibiting the activation of N-type calcium channel and, therefore, they are usable as remedies for the above-described diseases.
The calcium channels are now classified into subtypes L, N, P, Q, R and T. Each of the subtypes is distributed specifically to organs. Particularly, it is known that N-type calcium channel is widely distributed in the central nerves, peripheral nerves and adrenal medulla cells and that this calcium channel is concerned with the death of neurons, control of blood catecholamine dynamics and control of senses such as perceptivity.
It was confirmed that peptides, omega conotoxin GVIA and omega conotoxin MVIIA which selectively inhibit the function of N-type calcium channel inhibit the release of excitatory neurotransmitter from a brain slice sample. It was confirmed by animal experiments that they prevent the advancement of neuron necrosis in a cerebrovascular disorder. It is generally considered that a compound having a clinical effect of inhibiting the function of N-type calcium channel is effective in curing encephalopathies caused by the ischemia in the acute phase after the onset of cerebral infarction, cerebral hemorrhage (including subarachnoidal bleeding) or the like; progressive neurodegenerativediseases, e.g. Alzheimer""s disease; AIDS related dementia; Parkinson""s disease; dementia caused by cerebrovascular disorders and ALS; neuropathy caused by head injury. In addition, it was also confirmed by animal experiments that omega conotoxin MVIIA gets rid of formalin-caused sharp pain, hot plate pain, sharp pain caused by peripheral neuropathy, etc. Therefore, this medicine is considered to be clinically effective for relieving various pains such as sharp pain caused by spinal injury,diabetes or thromboangitis obliterans; pain after an operation; migraine; and visceral pain. Further, omega conotoxin GVIA inhibits the release of catecholamine from cultured sympathetic ganglion cells, the constriction reaction of an isolated blood vessel by the electric stimulation of governing nerves, and the acceleration of catecholamine secretion from dog adrenal medulla, etc. Therefore, it is considered that compounds having the N-type calcium channel-inhibiting activity are clinically effective in treating various diseases caused by psychogenic stress, e.g. bronchial asthma, unstable angina and hypersensitive colon inflammation [Neuropharmacol., 32, 1141 (1993)].
Although several peptide compounds and non-peptide compounds which selectively react on the N-type calcium channel have been disclosed hitherto (for example, WO 9313128), they are not yet used as practical medicines. Some of known compounds which react on the N-type calcium channel also react on other calcium channels than the N-type calcium channel [British Journal of Pharmacology, 122 (1), 37-42, 1997]. For example, compounds which are also antagonistic to L-type calcium channel, which deeply concern with the hypotensive effect, were incompatible with diseases for which N-type antagonists are efficacious (such as cerebral stroke, and pain caused of neuralgia, terminal cancer and spinal injury or the like).
An object of the present invention is to provide new compounds having a selectively antagonistic effect on N-type calcium channel.
Another object of the present invention is to provide antagonists to the N-type calcium channel.
Still another object of the present invention is to provide remedies for encephalopathies caused by the ischemia in the acute phase after the onset of cerebral infarction or cerebral hemorrhage, Alzheimer""s disease, AIDS related dementia, Parkinson""s disease, progressive neurodegenerative disease, neuropathy caused by head injury, sharp pain caused by thromboangitis obliterans, pain after operation, migraine, visceral pain, bronchial asthma, unstable angina, hypersensitive colon inflammation and drug addiction withdrawal symptoms.
The above-described objects and other objects of the present invention will be apparent from the following description and Examples.
The inventors synthesized various dihydropyridine derivatives, and made investigations on the effects of these newly synthesized compounds and known dihydropyridine derivatives for inhibiting the electric current of N-type calcium channel. After the investigations, the inventors have found that some specified, new dihydropyridine derivatives have excellent, selective antagonistic effect on the N-type calcium channel. The present invention has been completed on the basis of this finding.
Namely, the present invention provides dihydropyridine derivatives of following general formula (1) or pharmaceutically acceptable salts thereof: 
wherein A represents a group of following general formula (2), 1-naphthyl group, 2-naphthyl group, thiophene-2-yl group, furan-3-yl group, furan-2-yl group, pyridine-4-yl group, pyridine-3-yl group or pyridine-2-yl group: 
wherein R1, R3 and R5 may be the same or different from each other, and each represent hydrogen atom, a halogen atom, hydroxyl group, carboxyl group, amino group, cyano group, nitro group, a lower alkyl group, a lower alkoxyl group, a lower alkenyl group, a lower alkynyl group, a lower alkylamino group, a lower alkylthio group, a lower alkanoyl group, a hydroxy-lower alkyl group, a hydroxy-lower alkoxyl group, a hydroxy-lower alkenyl group, a halogeno-lower alkyl group, a halogeno-lower alkoxyl group, a halogeno-lower alkenyl group, an aryl-lower alkoxyl group, a lower alkoxycarbonyl group or an aroyl group, and
R2 and R4 may be the same or different from each other, and each represent hydrogen atom, a halogen atom, hydroxyl group, carboxyl group, amino group, cyano group, a lower alkyl group, a lower alkoxyl group, a lower alkenyl group, a lower alkynyl group, a lower alkylamino group, a lower alkylthio group, a lower alkanoyl group, a hydroxy-lower alkyl group, a hydroxy-lower alkoxyl group, a hydroxy-lower alkenyl group, a halogeno-lower alkyl group, a halogeno-lower alkoxyl group, a halogeno-lower alkenyl group, an aryl-lower alkoxyl group, a lower alkoxycarbonyl group or an aroyl group,
B represents carbamoyl group, cyano group, nitro group, acetyl group or carboxyl group,
C represents hydrogen atom, methyl group, ethyl group or dimethoxymethyl group,
D represents hydrogen atom, a lower alkyl group, a hydroxy-lower alkyl group or an aryl-lower alkyl group,
E represents hydrogen atom, methyl group, ethyl group, dimethoxymethyl group or cyano group,
F represents a group of following general formula (3), thiophene-3-yl group, thiophene-2-yl group, furan-3-yl group, furan-2-yl group, pyridine-4-yl group, pyridine-3-yl group or pyridine-2-yl group: 
wherein
R6, R7, R8, R9 and R10 may be the same o r different from each other, and each represent hydrogen atom, a halogen atom, hydroxyl group, carboxyl group, amino group, cyano group, nitro group, a lower alkyl group, a lower alkoxyl group, a lower alkenyl group, a lower alkynyl group, a lower alkylamino group, a lower alkylthio group, a lower alkanoyl group, a hydroxy-lower alkyl group, a hydroxy-lower alkoxyl group, a hydroxy-lower alkenyl group, a halogeno-lower alkyl group, a halogeno-lower alkoxyl group, a halogeno-lower alkenyl group, an aryl-lower alkoxyl group, a lower alkoxycarbonyl group or an aroyl group,
X represents an interatomic bond, xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94, and
Y represents a group of any of following general formulae (4) to (13): 
wherein two of R1 to R3 may be bonded together to form a ring.
The present invention also provides compounds of the above general formula (1) wherein A, C, D, E and X are as defined above,
R1, R2, R3, R4 and R5 may be the same or different from each other, and each represent hydrogen atom, a halogen atom, hydroxyl group, carboxyl group, cyano group, nitro group, a lower alkyl group, a lower alkoxyl group, a halogeno-lower alkyl group or a lower alkoxycarbonyl group, with the proviso that either R2 or R 4must be nitro group,
B represents carbamoyl group, nitro group or acetyl group,
F represents a group of general formula (3), cyclohexyl group, thiophene-3-yl group, thiophene-2-yl group, furan-3-yl group, furan-2-yl group, pyridine-4-yl group, pyridine-3-yl group or pyridine-2-yl group,
R6, R7, 8, R9 and R10 may be the same or different from each other, and each represent hydrogen atom, a halogen atom, hydroxyl group, carboxyl group, a lower alkyl group, a lower alkoxyl group or a lower alkoxycarbonyl group, and
Y represents a group of any of general formulae (4) to (12).
The present invention also provides an antagonist to the N-type calcium channel, which contains a dihydropyridine derivative of following general formula (1) or a pharmaceutically acceptable salt thereof as the active ingredient: 
wherein A represents a group of following general formula (2), 1-naphthyl group, 2-naphthyl group, thiophene-3-yl group, thiophene-2-yl group, furan-3-yl group, furan-2-yl group, pyridine-4-yl group, pyridine-3-yl group or pyridine-2-yl group: 
wherein
R1, R2, R3, R4 and R5 may be the same or different from each other, and each represent hydrogen atom, a halogen atom, hydroxyl group, carboxyl group, amino group, cyano group, nitro group, a lower alkyl group, a lower alkoxyl group, a lower alkenyl group, a lower alkynyl group, a lower alkylamino group, a lower alkylthio group, a lower alkanoyl group, a hydroxy-lower alkyl group, a hydroxy-lower alkoxyl group, a hydroxy-lower alkenyl group, a halogeno-lower alkyl group, a halogeno-lower alkoxyl group, a halogeno-lower alkenyl group, an aryl-lower alkoxyl group, a lower alkoxycarbonyl group or an aroyl group,
B represents carbamoyl group, cyano group, nitro group, acetyl group or carboxyl group,
C represents hydrogen atom, methyl group, ethyl group or dimethoxymethyl group,
D represents hydrogen atom, a lower alkyl group, a hydroxy-lower alkyl group or an aryl-lower alkyl group,
E represents hydrogen atom, methyl group, ethyl group, dimethoxymethyl group or cyano group,
F represents a group of following general formula (3), cyclohexyl group, thiophene-3-yl group, thiophene-2-yl group, furan-3-yl group, furan-2-yl group, pyridine-4-yl group, pyridine-3-yl group or pyridine-2-yl group: 
wherein
R6, R7, R8, R9 and R10 may be the same or different from each other, and each represent hydrogen atom, a halogen atom, hydroxyl group, carboxyl group, amino group, cyano group, nitro group, a lower alkyl group, a lower alkoxyl group, a lower alkenyl group, a lower alkynyl group, a lower alkylamino group, a lower alkylthio group, a lower alkanoyl group, a hydroxy-lower alkyl group, a hydroxy-lower alkoxyl group, a hydroxy-lower alkenyl group, a halogeno-lower alkyl group, a halogeno-lower alkoxyl group, a halogeno-lower alkenyl group, an aryl-lower alkoxyl group, a lower alkoxycarbonyl group or an aroyl group,
X represents an interatomic bond, xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94, and
Y represents a group of any of following general formulae (4) to (16): 
wherein two of R1 to R3 may be bonded together to form a ring.
The present invention further provides a medicine containing the above-described dihydropyridine derivative or a pharmaceutically acceptable salt thereof as the active ingredient, and usable for any of encephalopathies caused by the ischemia in the acute phase after the onset of cerebral infarction, cerebral hemorrhage, Alzheimer""s disease, AIDS related dementia, Parkinson""s disease, progressive neurodegenerative disease, neuropathy caused by head injury, sharp pain caused by thromboangitis obliterans, pain after an operation, migraine and visceral pain, bronchial asthma, unstable angina, hypersensitive colon inflammation, and drug addiction withdrawal symptoms.
The present invention also provides a medicinal composition containing the above-described dihydropyridine derivative or a pharmaceutically acceptable salt thereof, a carrier and/or a diluent.
The term xe2x80x9clowerxe2x80x9d herein indicates that the group has 1 to 6 carbon atoms. The alkyl groups themselves and the alkyl groups in the alkoxyl, alkenyl, alkylamino, alkylthio and alkanoyl groups may be either linear or branched. The alkyl groups are, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group and secondary and tertiary butyl groups. Among them, those having 1 to 3 carbon atoms are preferred. The aryl-lower alkoxyl groups include, for example, benzyloxy group. The halogen atoms indicate fluorine, chlorine, bromine and iodine atoms. Examples of the aryl groups include phenyl group and substituted phenyl groups, and the substituents thereof are particularly halogens, alkyl groups and alkoxyl groups. Examples of the aroyl groups include benzoyl group and pyridylcarbonyl group.
In general formula (2) for the medicine containing the above-described dihydropyridine derivative or a pharmaceutically acceptable salt thereof as the active ingredient, and usable for any of N-type calcium channel antagonists, encephalopathies caused by the ischemia in the acute phase after the onset of cerebral infarction, cerebral hemorrhage, Alzheimer""s disease, AIDS related dementia, Parkinson""s disease, progressive neurodegenerative disease, neuropathy caused by head injury, sharp pain caused by thromboangitis obliterans, pain after an operation, migraine and visceral pain, bronchial asthma, unstable angina and hypersensitive colon inflammation, and drug addiction withdrawal symptoms, R1, R2, R3, R4 and R5 may be the same or different from each other, and each preferably represent hydrogen atom, a halogen atom, hydroxyl group, carboxyl group, cyano group, nitro group, a lower alkyl group, a lower alkoxyl group, a halogeno-lower alkyl group or a lower alkoxycarbonyl group.
Preferably, A in general formula (1) is represented by general formula (2) wherein R1, R3, R4 and R5 each represent hydrogen atom, and R2 represents chlorine atom, bromine atom, iodine atom or cyano group, B represents carboxyl group, C represents methyl group, D represents hydrogen atom, E represents methyl group, F represents phenyl group, X represents an interatomic bond, and Y is represented by general formula (11).
In the present invention, preferreddihydropyridine derivatives are those of general formula (1) or pharmaceutically allowable salts thereof, wherein R1, R3 and R5 in general formula (2) may be the same or different from each other, and they each represent hydrogen atom, a halogen atom, hydroxyl group, carboxyl group, cyano group, nitro group, a lower alkyl group, a lower alkoxyl group, a halogeno-lower alkyl group or a lower alkoxycarbonyl group, and
R2 and R4 may be the same or different from each other, and they each represent hydrogen atom, a halogen atom, hydroxyl group, carboxyl group, cyano group, a lower alkyl group, a lower alkoxyl group, a halogenoalkyl group or a lower alkoxycarbonyl group (preferred embodiment I).
Preferably, D is hydrogen atom, X is the interatomic bond and Y is the group of formula(11).
B is preferably carboxyl group.
In preferred embodiment I, A is represented by general formula (2) wherein R1, R3, R4 and R5 each represent hydrogen atom, and R2 represents chlorine atom, bromine atom, iodine atom or cyano group, B represents carboxyl group, C represents methyl group, D represents hydrogen atom, E represents methyl group, F represents phenyl group and X represents the interatomic bond.
Also preferably, A is represented by general formula (2) wherein R1, R3, R4 and R5 each represent hydrogen atom, and R2 represents chlorine atom, bromine atom, iodine atom or cyano group, B represents carboxyl group, C represents methyl group, D represents hydrogen atom, E represents methyl group, F represents phenyl group and Y is represented by formula (11).
Preferably, A is represented by general formula (2) wherein R1, R3, R4 and R5 each represent hydrogen atom, and R2 represents chlorine atom, bromine atom, iodine atom or cyano group, C represents methyl group and E represents methyl group.
Preferably, A is represented by general formula (2) wherein R1, R3, R4 and R5 each represent hydrogen atom, and R2 represents chlorine atom, bromine atom, iodine atom or cyano group, C represents hydrogen atom or methyl group and F represents phenyl group.
In preferred embodiment I, A is represented by general formula (2) wherein R1, R3, R3 and R5 each represent hydrogen atom, and R2 represents chlorine atom, bromine atom, iodine atom or cyano group, B represents carboxyl group, C represents methyl group, E represents methyl group, F represents phenyl group, X represents the interatomic bond and Y is represented by formula (11).
Preferably, A is represented by general formula (2) wherein R1, R3, R4 and R5 each represent hydrogen atom, and R2 represents chlorine atom, bromine atom, iodine atom or cyano group, E represents methyl group and F represents phenyl group.
Preferably, A is represented by general formula (2) wherein R1, R3, R4 and R5 each represent hydrogen atom, and R2 represents chlorine atom, bromine atom, iodine atom or cyano group, C represents methyl group, E represents methyl group and F represents phenyl group.
Preferably, C represents methyl group, E represents methyl group and F represents phenyl group.
Preferably, A is represented by general formula (2) wherein R1, R3, R4 and R5 each represent hydrogen atom, and R2 represents chlorine atom, bromine atom, iodine atom or cyano group.
Preferred dihydropyridine derivatives or pharmaceutically acceptable salts thereof are those of the general formula (1) wherein A represents a group of above general formula (2) wherein R1 and R3 may be the same or different from each other, and each represent hydrogen atom, a halogen atom, hydroxyl group, amino group, nitro group, a lower alkyl group, a lower alkoxyl group, a lower alkenyl group, a lower alkylamino group, a lower alkylthio group, a lower alkanoyl group, a hydroxy-lower alkyl group, a hydroxy-lower alkoxyl group, a hydroxy-lower alkenyl group, a halogeno-lower alkyl group, a halogeno-lower alkoxyl group, a halogeno-lower alkenyl group, an aryl-lower alkoxyl group or an aroyl group,
R2 represents hydrogen atom, a halogen atom, hydroxyl group, amino group, a lower alkyl group, a lower alkoxyl group, a lower alkenyl group, a lower alkylamino group, a lower alkylthio group, a lower alkanoyl group, a hydroxy-lower alkyl group, a hydroxy-lower alkoxyl group, a hydroxy-lower alkenyl group, a halogeno-lower alkyl group, a halogeno-lower alkoxyl group, a halogeno-lower alkenyl group, an aryl-lower alkoxyl group or an aroyl group, and R4 and R5 each represent hydrogen atom, with the proviso that two of R1 to R3 may form a ring together,
B represents carboxyl group,
C represents methyl group,
D represents hydrogen atom, a lower alkyl group, a hydroxy-lower alkyl group or an aryl-lower alkyl group,
E represents methyl group,
F represents a group of general formula (3) wherein R6, R7, R8, R9 and R10 may be the same or different from each other, and each represent hydrogen atom, a halogen atom, hydroxyl group, amino group, nitro group, a lower alkyl group, a lower alkoxyl group, a lower alkenyl group, a lower alkylamino group, a lower alkylthio group, a lower alkanoyl group, a hydroxy-lower alkyl group, a hydroxy-lower alkoxyl group, a hydroxy-lower alkenyl group, a halogeno-lower alkyl group, a halogeno-lower alkoxyl group, an aryl-lower alkoxyl group or an aroyl group, X represents an interatomic bond, and Y represents a group of formula (5), (11) or (12).
The present invention further provides an N-type calcium channel antagonist, a medicinal composition and a medicine containing the above-described, preferred dihydropyridine derivative or a pharmaceutically acceptable salt thereof as the active ingredient, and usable for any of encephalopathies caused by the ischemia in the acute phase after the onset of cerebral infarction, cerebral hemorrhage, Alzheimer""s disease, AIDS related dementia, Parkinson""s disease, progressive neurodegenerative disease, neuropathy caused by head injury, sharp pain caused by thromboangitis obliterans, pain after an operation, migraine and visceral pain, bronchial asthma, unstable angina, hypersensitive colon inflammation, and drug addiction withdrawal symptoms.
Thedihydropyridine derivatives (1) of the present invention can be produced by processes described below.
For example,dihydropyridine derivatives (1-1) wherein D is hydrogen atom and B is carboxyl group can be produced according to the following flow chart: 
wherein A, F, X and Y are as defined above.
Namely, a dihydropyridinedicarboxylic acid diester (22) can be obtained by reacting an aldehyde (17), a 3-aminocrotonic ester (18) and 2-cyanoethyl acetoacetate (19), or by reacting the aldehyde (17), an acetoacetic ester (20) and 2-cyanoethyl 3-aminocrotonate (21). Then the dihydropyridinedicarboxylic acid diester thus obtained is treated with a base such as sodium hydroxide to obtain a dihydropyridinecarboxylic acid derivative (1-1) of the present invention.
Further, the dihydropyridine derivatives (1-1) can be obtained according to the following flow chart: 
Namely, a cyanoethyl benzyl dihydropyridinedicarboxylate (24) can be obtained by reacting an aldehyde (17), benzyl acetoacetate (23) and 2-cyanoethyl 3-aminocrotonate (21). Then the obtained ester (24) is hydrogenated in ethyl acetate in the presence of a palladium catalyst to obtain monocyanoethyl dihydropyridinedicarboxylate (25). This ester (25) is reacted with an alcohol (26) in the presence of a condensing agent such as WSC to obtain a dihydropyridinedicarboxylic acid diester (22), which is then treated with a base such as sodium hydroxide to obtain a dihydropyridinecarboxylic acid derivative (1-1) of the present invention.
Dihydropyridinecarboxylic acid derivatives (1-2) wherein the substituent of the ester is a carboxyl group-substituted cinnamyl can be obtained by the following process: 
Namely,dihydropyridinecarboxylic acid derivatives (1-2) of the present invention can be produced by subjecting a dihydropyridinedicarboxylic ester (28) to Heck reaction in the presence of a palladium catalyst and then treating the reaction product with a base such as sodium hydroxide.
Dihydropyridine derivatives (1-3) wherein B is carbamoyl group can be produced by reacting an aldehyde (17), a 3-aminocrotonic ester (18) and acetoacetamide (31) according to the following flow chart: 
wherein A, D, F, X and Y are as defined above.
Dihydropyridine derivatives (1-4) wherein B is cyano group can be produced by reacting an aldehyde (17), an acetoacetic ester (20) and 3-aminocrotonitrile (32) according to the following flow chart: 
Dihydropyridine derivatives (1-5) wherein B is nitro group can be produced by reacting an aldehyde (17), a 3-aminocrotonic ester (18) and nitroacetone (33) according to the following flow chart: 
wherein A, D, F, X and Y are as defined above.
Dihydropyridine derivatives (1-6) wherein B is acetyl group can be produced by reacting an aldehyde (17), a 3-aminocrotonic ester (18) and acetylacetone (34) according to 5 the following flow chart: 
wherein A, D, F, X and Y are as defined above.
Dihydropyridine derivatives (1-7) wherein D is a substituent other than hydrogen atom and B is carboxyl 25 group can be produced by, for example, as follows: An aldehyde (17), a 3-aminocrotonic ester (18) and 2-trimethylsilylethyl acetoacetate (35) are reacted together to obtain adihydropyridinedicarboxylicdiester (36), which is then reacted with an alkyl halide or the like in the 30 presence of a base such as sodium hydride to obtain a product (37), which is treated with, for example, tetrabutylammonium fluoride to obtain a dihydropyridine derivative (1-7) wherein D is substituted. 
wherein A, D, F, X and Y are as defined above.
Dihydropyridine derivatives (1-8) wherein E is hydrogen atom can be produced from, for example, an acetylenecarboxylic ester (38) according to the following flow chart: 
wherein A, F, X and Y are as defined above.
Dihydropyridine derivatives (1-9) wherein C is hydrogen atom can be produced from, for example, an acetylenecarboxylic ester (41) according to the following flow chart: 
wherein A, F, X and Y are as defined above.
Dihydropyridine derivatives (1-10) wherein both C and E are each hydrogen atom can be produced from, for example, acetylenecarboxylic esters (38) and (41) according to the following flow chart: 
wherein A, F, X and Y are as defined above.
Dihydropyridine derivatives (1-11) wherein E is ethyl group can be produced from, for example, 3-oxovaleric esters (45) according to the following flow chart: 
wherein A, F, X and Y are as defined above.
Dihydropyridine derivatives (1-12) wherein C is ethyl group can be produced from, for example, trimethylsilyl 3-oxovaleric ester (47) according to the following flow chart: 
wherein A, F, X and Y are as defined above.
Dihydropyridine derivatives (1-13) wherein E is dimethoxymethyl group can be produced from, for example, ketoesters (49) according to the following flow chart: 
wherein A, F, X and Y are as defined above.
Dihydropyridine derivatives (1-14) wherein E is cyano group can be produced according to the following flow chart. Namely, they can be produced by the acid treatment of dihydropyridine diesters (51) with an acid, followed by the conversion of the product into an oxime, dehydration reaction and hydrolysis. 
wherein A, F, X and Y are as defined above.
When 3-aminocrotonic esters (18) used as the starting materials are not well-known, they can be produced by, for example, heating an alcohol (26) with a diketene (54) and a suitable base to obtain an acetoacetic ester (20) and then reacting the ester (20) with an amine or ammonium acetate. 
wherein D, F and Y are as defined above.
When the compounds of general formula (1) of the present invention can form salts, the salts must be pharmaceutically acceptable ones. The salts are ammonium salts, salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, aluminum salts, zinc salts, salts with organic amines such as morpholine and piperidine, and salts with basic amino acids such as arginine and lysine.
The compounds of general formula (1) or salts thereof can be administered as they are or in the form of various medicinal compositions. The forms of the medicinal compositions are, for example, tablets, powders, pills, granules, capsules, suppositories, solutions, sugar-coated tablets and depots. They can be prepared with an ordinary assistants such as carriers and diluents. For example, tablets can be prepared by mixing the dihydropyridine derivative used as the active ingredient of the present invention with a known assistant material such as an inert diluent, e.g. lactose, calcium carbonate or calcium phosphate; a binder, e.g. acacia, corn starch or gelatin; an excipient, e.g. alginic acid, corn starch or pregelatinized starch; a sweetening agent, e.g. sucrose, lactose or saccharin; a flavoring agent, e.g. peppermint, or cherry; and magnesium stearate, talc or carboxymethylcellulose.
The N-type calcium channel antagonists containing one of the compounds of general formula (1) and salts thereof are usable as therapeutic agents for any of encephalopathies caused by the ischemia in the acute phase after the onset of cerebral infarction, cerebral hemorrhage (including subarachnoidal bleeding) or the like; progressive neurodegenerativediseases, e.g. Alzheimer""s disease; AIDS related dementia; Parkinson""s disease; dementia caused by cerebrovascular disorders and ALS; various pains, e.g. oneuropathy caused by head injury; sharp pain caused by spinal injury,diabetes or thromboangitis obliterans; pain after an operation; migraine and visceral various diseases caused by psychogenic stress, e.g. pain; bronchial asthma; unstable angina and hypersensitive colon inflammation; emotional disorder; and drug addiction withdrawal symptoms, e.g. ethanol addiction withdrawal symptoms.
The dosage of the therapeutic agent used for the above-described purpose varies depending on the intended therapeutic effect, method of administration, period of therapy, age, body weight, etc. Usually, it is given to adults in an amount of 1 xcexcg to 5 g/day in the oral administration, and 0.01 xcexcg to 1 g/day in the parenteral administration.